MAST1 is neuron-specific regulator of mitochondrial trafficking and abundance in human brain tissue

MAST1 de novo mutations in human neurons are linked to impaired neurite outgrowth and mitochondrial dysfunction, including increased hyperactive mitochondria and reactive oxygen species accumulation.

• Why it matters: Neuronal development needs mitochondria at distal axons and dendrites, but the mechanisms controlling mitochondrial trafficking and mitochondrial abundance in human neurons are not well defined.
• What they did: The study analyzed rare de novo MAST1 variants in patients with multiple neurodevelopmental abnormalities using induced pluripotent stem cell-derived telencephalic brain organoids and patient cortical neurons, plus engineered lines, then tested rescue by expressing wild-type MAST1 or treating with creatine or N-acetyl-L-cysteine.
• The result: MAST1 mutations altered MAST1–mitochondria interactions and disrupted mitochondrial trafficking and abundance, and wild-type MAST1 expression or prolonged creatine/N-acetyl-L-cysteine treatment rescued neurite outgrowth, implying a role in microcephaly-associated neuronal mitochondrial dysfunction and neuronal loss.

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